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The treatment of elderly advanced non-small cell lung cancer (NSCLC) patients presents many challenges. Patients in this age group are often under-represented in clinical trials or undertreated because of issues such as co-morbidities, poor performance status, or potential therapy-related toxicities.

In a recent phase III trial, one subset of NSCLC patients 70 years of age or older was evaluated with carboplatin and either conventional (solvent-based) paclitaxel or nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) doublet therapy (Ann Oncol 2013;24:314-321). In this study, it was shown that those treated with NAB-paclitaxel/carboplatin had a significantly longer overall survival (OS) than those treated with the conventional solvent-based paclitaxel/carboplatin doublet therapy.

To more fully explore the treatment options of NAB-paclitaxel/carboplatin in this elderly NSCLC patient subset, Corey J. Langer, MD, Director of Thoracic Oncology, Hospital of the University of Pennsylvania, Philadelphia, and colleagues conducted the ABOUND.70+ clinical trial. This study evaluated the use of NAB-paclitaxel/carboplatin with both continuous and 3 weeks on/1 week off dosing schedules in treatment-naïve NSCLC patients 70 years of age or older. Researchers presented their findings at the 2017 ASCO Annual Meeting (Abstract 9059).

NAB-Paclitaxel

The protein-bound paclitaxel (NAB-paclitaxel) formulation was developed to improve the therapeutic index of the antineoplastic taxane. A phase III trial was conducted by Socinski, et al, that evaluated the use of carboplatin every 3 weeks with either NAB-paclitaxel (NAB-P/C) administered weekly or solvent-based (sb) paclitaxel (sb-P/C) given every 3 weeks in a group of 1,052 untreated stage IIIB/IV NSCLC patients who were stratified by age (85% <70, 15% ≥70).

The conventional sb-P/C regimen consisted of 200 mg/m2 paclitaxel and AUC 6 carboplatin on day 1 of a 21-day cycle (q3w), while the NAB-P/C regimen consisted of 100 mg/m2 NAB-paclitaxel on days 1, 8, and 15 and AUC 6 carboplatin on day 1 of a 21-day cycle. The primary endpoint for this study was overall response rate (ORR), while progression-free survival (PFS) and overall survival (OS) were secondary endpoints.

In patients 70 years of age or older, the ORR was higher in the NAB-P/C arm (34% vs. 24%). The median PFS was also longer for the NAB-P/C arm in these elderly patients (8.0 vs. 6.8 months); however, a large difference was noted in the OS data. In this analysis, the median OS for those 70 or older was significantly longer for the NAB-P/C arm relative to the sb-P/C arm (19.9 vs. 10.4 months).

From these data, the investigators concluded that in elderly advanced NSCLC patients weekly NAB-P/C was well-tolerated as a first-line therapy, and there was some improvement noted in the ORR and median PFS data as well as significant improvement in the median OS relative to the sb-P/C regimen.

ABOUND.70+

Abstract 9059

The goal of this study was to assess the safety and efficacy of continuously-dosed NAB-P/C in comparison to a regimen in which a 1-week break followed each 3-week dosing cycle in a group of treatment-naïve advanced NSCLC patients who were 70 or older. To accomplish this, patients were randomized in a 1:1 fashion to receive either continuously-dosed NAB-paclitaxel (100 mg/m2 via 30 min infusion on days 1, 8, and 15) and carboplatin (AUC 6, day 1) with a q3w schedule (Arm A) or the same 3-week dosing cycle (NAB-paclitaxel 100 mg/m2, days 1, 8, and 15 and carboplatin-AUC 6, day 1) followed by a 1-week break between dosing cycles (Arm B). Treatment was continued until disease progression or unacceptable toxicity was noted. The planned accrual for this study was 284 patients. Patients were stratified according to ECOG performance status and histology.

The primary endpoint for this study was to assess the safety of these regimens comparing the percentage of patients with peripheral neuropathy (grade 2 or higher) and myelosuppression (grade 3 or higher) in each arm. Secondary endpoints included PFS, OS, ORR, and safety (i.e., adverse events).

Methodology

The data cutoff date in this study was Nov. 20, 2016. Peripheral neuropathy and myelosuppression (determined by local lab values for hemoglobin, platelet, and absolute neutrophil counts) were assessed at baseline, days 1, 8, and 15 of each dosing cycle and 28 days after last treatment.

The intent-to-treat population (all patients randomized) was utilized for efficacy analyses, while the treated population (those receiving one or more doses of the investigational drug) was used for safety assessment. Both response and progression data were measured using RECIST v. 1.1 methodology. CT scans were performed every 42 days until progression was observed.

Baseline Patient Characteristics

In Arm A (N = 71), the median patient age was 76 (range – 70-87), while for Arm B (N = 72), the median age was 75 (range – 70-93). Arm A consisted of 41 males (58%) and 30 females (42%); Arm B included 40 males (56%) and 32 females (44%). The majority of patients had stage IV NSCLC at enrollment in this trial (Arm A – 85%; Arm B – 82%).

One characteristic that was utilized to stratify patients was disease histology. In Arm A, there were 44 patients with non-squamous and 27 with squamous histology, while for Arm B there were 44 with non-squamous and 28 with squamous histology. In addition to histology, ECOG performance status (PS) was also used to stratify patients. In Arm A, there were 21 patients with a PS of 0 and 50 with a score of 1, and in Arm B, there were 20 patients with a PS score of 0 and 52 patients with a PS of 1.

Results

With respect to the primary endpoint in this study, there was no significant difference found between the two arms. In Arm A, there were 68 patients used for this analysis, and of these, 25 (37%) displayed grade 2 or higher peripheral neuropathy while 48 (71%) had grade 3 or higher myelosuppression. A total of 52 patients (76%) in this arm met one or both of these criteria. For Arm B (the dose-interrupted regimen), 70 patients were evaluated for primary endpoint analysis and, of these, 25 (36%) had grade 2 or higher peripheral neuropathy and 45 (64%) had grade 3 or higher myelosuppression. A total of 54 patients (77%) had one or both of these conditions.

The patients in Arm B had a longer PFS, with a median value of 6.97 months (95% CI – 5.85-12.22 months), whereas those in Arm A had a median PFS of 3.58 months (95% CI – 3.02-6.24 months); the hazard ratio (HR) for this difference was 0.48 (95% CI – 0.30-0.76; P = 0.0019).

The OS for both groups was somewhat similar, with Arm A having a median OS of 15.18 months (95% CI – 10.51-17.51 months) while Arm B had a median OS of 16.23 months (95% CI – 12.85 months-not evaluable) for a HR of 0.72 (95% CI – 0.44-1.19; P = 0.1966).

Patients in Arm A of this study (N=71) had an ORR of 24 percent (95% CI – 14.6-35.5%) with one patient showing complete response (CR) and 16 having partial response (PR). The ORR for Arm B (N=72) was 40 percent (95% CI – 28.9-52.5%) with one patient having CR and 28 exhibiting a PR. Stable disease was noted in 52 percent of the patients in Arm A and 43 percent of the patients in Arm B.

Discussion

“The results obtained in our study clearly showed that NAB-paclitaxel/carboplatin is an effective and well-tolerated chemotherapy regimen for advanced NSCLC patients 70 years or older. The median OS data were similar for both groups; however, Arm B, with the 3 weeks on/1 week off dosing regimen, did have a longer median PFS as well as a higher ORR compared to the continuous dosing regimen,” Langer explained.

“The improvement in Arm B with regards to the ORR and PFS data are most likely due to higher exposure of the investigational treatments; if the patients are better able to tolerate their therapy, then they are more likely to continue taking their medication. The patients in Arm A had a median of 4.0 cycles of treatment, whereas those in Arm B had a median of 5.5 cycles, and this translated to median treatment durations of 5.17 months for Arm B and 3.04 months for Arm A,” Langer stated. “The patients in Arm B also had higher median cumulative dose of NAB-paclitaxel relative to their Arm A counterparts (1287.5 vs. 875.0 mg/m2).”

When asked whether enrollment to this trial was still ongoing, Langer replied, “at the interim evaluation, when similar results for the primary endpoint (grade 2 or higher peripheral neuropathy and grade 3 or higher myelosuppression) were noted for both treatment arms, the decision was made to bring an early closure to enrollment.

“More investigations need to be done, but from this study, it appears that a dosing regimen with a weekly break between therapy cycles is feasible in this patient subpopulation. Compared to historic controls, therapeutic outcomes look promising,” Langer concluded.